'Facts' of C. Diff Transmission Challenged

by Michael Smith Michael Smith North American Correspondent, MedPage Today
September 25, 2013

Action Points

Note that this genetic analysis of C. difficile isolates from Oxfordshire, England, suggests that the majority of C. diff transmission may not arise from symptomatic hospitalized patients.

Be aware that the study relies on some assumptions about the mutation rate of C. diff strains that may require larger validation.

A sophisticated genetic analysis of Clostridium difficile cases is challenging the conventional wisdom that symptomatic patients are responsible for most transmission in hospitals.

Whole-genome sequencing of C. difficile isolates from more than 1,200 patients found that only 35% were related to a previous case in a large, four-hospital study, according to David Eyre, BMBCh, of John Radcliffe Hospital in Oxford, England, and colleagues.

The study is "impressive" and the results "challenge the traditional concept that symptomatic patients in hospitals account for most C. difficile transmission and infection," commented Curtis Donskey, MD, of the VA Medical Center in Cleveland.

In an accompanying editorial, he cautioned that the findings won't alter current recommendations for basic infection control measures, such as isolating symptomatic patients.

But the study suggests that they will not be enough: "Control of C. difficile will require that we move beyond the usual suspects," Donskey concluded.

Indeed, Kathleen Mullane, DO, PharmD, also of the University of Chicago, concurred. "We have to think of the community as being a large reservoir for this infection, as well as the hospital," she told MedPage Today.

The pathogen has become an increasing problem in recent years. Just this month, a study reported rates of disease attributed to C. difficile doubled in a decade.

And, in a call for action on antibiotic resistance, the CDC listed C. difficile as an urgent problem -- not because the pathogen is itself resistant, but because the disease it causes arises from overuse of antimicrobial agents.

From September 2007 through March 2011, using enzyme immunoassays for C. difficile toxins A and B, Eyre and colleagues tested all symptomatic patients in Oxfordshire, England, either in healthcare settings or in the community.

Of the 1,250 who tested positive for the pathogen, Eyre and colleagues were able to get a whole-genome sequence of 1,223 isolates, 957 of them from April 2008 through March 2011.

Examining first and last samples from a subset of 145 patients yielded an estimate of how quickly the pathogen was evolving, which, in turn, allowed the investigators to identify plausible epidemiological links among closely related isolates from different patients.

The investigators argued that sequences that differed by no more than two single nucleotide changes were likely related, while those with more than 10 were probably unrelated.

Of the 957 isolates, 333 (35%), had no more than two single nucleotide changes from at least one previous case, including those isolated earlier, from September 2007 to the end of March 2008.

But 428 isolates (45%) had more than 10 such differences from all previous isolates and were regarded as unrelated. The remaining isolates had an intermediate number of changes and couldn't be clearly defined as either related or unrelated.

Interestingly, they reported, of the 333 patients with sequences consistent with transmission, 126 had close hospital contact with another patient, but 120 had no such contact in a hospital or in the community.

The study probably underestimates the incidence of C. difficile in the local region, Mullane noted, because the tests Eyre and colleagues used for the bacterial toxins are outdated.

At her institution, she said, moving to newer, more sensitive tests -- polymerase chain reaction or nucleic acid tests -- led to an apparent doubling of C. difficile incidence.

The study is "among the first and largest of its kind" and moves the field forward, commented Sahil Khanna, MBBS, of the Mayo Clinic in Rochester, Minn.

While previous studies have suggested alternate transmission modes, they have been based on "potentially incomplete" epidemiologic data, Khanna told MedPage Today by email.

Clinically, he added, the data suggest doctors should suspect C. difficile in patients with diarrhea even if they don't have traditional risk factors, such as recent antibiotic use.

How well the findings apply to the U.S. is also a question, commented Alan Stamm, MD, of the University of Alabama Birmingham. He noted that patients in the study were usually housed in four-bed bays, a practice that's unusual in the U.S.

"Most patients here are in private rooms with private bathrooms (and) there is much less opportunity for patient-to-patient contact," Stamm told MedPage Today in an email, so there might be "even less opportunity" for transmission in American hospitals.

He added that the study was done during a period -- 2007 to 2011 -- when precautions against C. difficile transmission were widely used, which might have reduced the impact of symptomatic patients.

"This is an important article," he said, "but it raises more questions than it answers."

The study had support from the National Institute for Health Research, the United Kingdom Clinical Research Collaboration Modernising Medical Microbiology Consortium, the Medical Research Council, the Biotechnology and Biological Sciences Research Council, the Department of Health, and the Wellcome Trust. Eyre did not report any conflicts.

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